CN117062805A - Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid - Google Patents

Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid Download PDF

Info

Publication number
CN117062805A
CN117062805A CN202280023580.9A CN202280023580A CN117062805A CN 117062805 A CN117062805 A CN 117062805A CN 202280023580 A CN202280023580 A CN 202280023580A CN 117062805 A CN117062805 A CN 117062805A
Authority
CN
China
Prior art keywords
chloro
fluoro
acid
formula
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202280023580.9A
Other languages
Chinese (zh)
Inventor
M·格拉巴尼克
A·K·基哈
R·V·盖尔格
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Adama Agan Ltd
Original Assignee
Adama Agan Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Adama Agan Ltd filed Critical Adama Agan Ltd
Publication of CN117062805A publication Critical patent/CN117062805A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/16—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/58—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a novel process for the nitration of 2-chloro-4-fluorobenzoic acid to 2-chloro-4-fluoro-5-nitrobenzoic acid, 2-chloro-4-fluoro-3-nitrobenzoic acid and 3, 5-dinitro-2-chloro-4-fluorobenzoic acid; purifying the crude reaction product; and recovering 2-chloro-4-fluoro-5-nitrobenzoic acid in a substantially pure form useful in the synthesis of the herbicide pyribenzoxim.

Description

Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid
Pyribenzoxim (chemical name: 2-chloro-4-fluoro-5- [ 3-methyl-2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl)]-N- [ methyl (propan-2-yl) sulfamoyl]Benzamide) is a uracil (amide) herbicide. Pyribenzoxim is a pre-plant and pre-emergence herbicide that is applied to a wide range of food crops alone or in combination with glyphosate [ see PPDB (database of pesticide characteristics created by university of herford) (Pesticide Properties Database)https://sitem.herts.ac.uk/aeru/ppdb/en/index.htm)]。
Pyribenzoxim is first described in WO 01/83459. The multistep synthesis of pyribenzoxim involves the nitration of 2-chloro-4-fluorobenzoic acid to give 2-chloro-4-fluoro-5-nitrobenzoic acid. As reported in example 1 of WO 01/83459, this reaction occurs in sulfuric acid by the addition of nitric acid. The reaction illustrated in WO 01/83459 shows 2-chloro-4-fluoro-5-nitrobenzoic acid as the sole reaction product:
in fact, this reaction produces a mixture of isomers, i.e. mononitration occurs at the 5-or 3-position of the aromatic ring:
hereinafter, 2-chloro-4-fluoro-5-nitrobenzoic acid and 2-chloro-4-fluoro-3-nitrobenzoic acid are referred to as a desired isomer and an undesired isomer, respectively. The amount of undesired isomer is not insignificant, for example, the crude reaction product typically consists of about 85-90:10-15 isomer mixtures. Unfortunately, the undesired isomer is not easily separated from the crude product. The experimental results reported below show that purification of about 85-90:10-15 isomer mixtures by crystallization to recover the desired isomer can only be achieved with unacceptably large proportions of solvents and products. Multi-step crystallization also encounters difficulty.
We have found that the mononitration reaction conditions of 2-chloro-4-fluorobenzoic acid can be altered to promote dinitration side reactions which occur almost exclusively on the undesired isomer. That is, the dinitro by-product, i.e., 3, 5-dinitro-2-chloro-4-fluorobenzoic acid, is obtained by consuming the undesired isomer. The undesired 3-nitro isomer rapidly undergoes continuous aromatic nitration at the 5-position, while the desired isomer does not react with the nitrating agent. Hereinafter, the by-product of 3, 5-dinitro-2-chloro-4-fluorobenzoic acid is designated as "3, 5-dinitro by-product".
The conversion of the undesired isomer into dinitration is beneficial because the resulting 3, 5-dinitro by-product demonstrates an increase in solubility in some types of organic solvents as compared to the mononitration isomer. Thus, unlike the undesired isomer which is difficult to remove, the 3, 5-dinitro by-product can be easily separated from the crude product by crystallization. For example, a crude product consisting of a mixture of the desired isomer: undesired isomer: about 85-90:3-9:9-3 ratio of 3, 5-dinitro by-product (HPLC, area%) can be purified by crystallization from, for example, an alkylated aromatic solvent in an efficient manner to recover the desired isomer in substantially pure form. As indicated above, the desired isomer is a useful intermediate, for example, in the synthesis of compounds having herbicidal activity.
The present invention therefore generally relates to a method comprising: reacting 2-chloro-4-fluorobenzoic acid with a nitrating agent;
separating a crude reaction product consisting of 2-chloro-4-fluoro-5-nitrobenzoic acid, 2-chloro-4-fluoro-3-nitrobenzoic acid and 3, 5-dinitro-2-chloro-4-fluorobenzoic acid;
purifying the crude reaction product; and
obtaining 2-chloro-4-fluoro-5-nitrobenzoic acid in substantially pure form.
The reaction is carried out under conditions that promote mononitration as a main reaction and dinitration as a side reaction. One set of conditions that allow for effective management of the mononitration/dinitration reaction includes the nitrating agent, the reaction temperature and the reaction time to adjust the ratio between the desired isomer, the undesired isomer and the dinitro by-product. Ratios (area% based on HPLC analysis) of the undesired isomer to 3, 5-dinitro by-product in the range of 3:1 to 1:3, e.g., 3:1 to 1:2, are generally satisfactory. A greater proportion of dinitro by-product indicates that the desired isomer has reacted with the nitrating agent, resulting in a yield loss. Thus, the above ratio balances the benefits obtained by converting the undesired isomer into readily separable byproducts with the yield loss of the desired isomer. HPLC conditions are described in the experimental section below.
The nitration of 2-chloro-4-fluorobenzoic acid is preferably carried out with a nitric acid/sulfuric acid mixture. The reaction vessel was charged with concentrated sulfuric acid, followed by the addition of the starting material 2-chloro-4-fluorobenzoic acid, which was readily soluble in sulfuric acid at room temperature to provide a clear solution. The concentration of starting material in sulfuric acid is adjusted to provide a stirrable reaction mixture, typically no more than 25%.
The addition of nitric acid to the mixture of sulfuric acid and starting material is carried out gradually with cooling, the temperature being maintained at about room temperature during the addition (addition accompanied by heat release). Nitric acid may be supplied to the reaction in a commercially available grade form of 70% to 98%. It is also possible to use a previously prepared mixed acid reagent (H 2 SO 4 /HNO 3 ) For example, a mixture that is typically in equal proportions. The nitric acid is used in a molar excess to enable dinitration to the desired extent, for example in the range of 1.25 to 2.0 equivalents of nitric acid, preferably in the range of 1.4 to 1.8, such as about 1.5 equivalents (i.e. at least 25% molar excess relative to the starting material, for example 25% to 100%, or 40% to 80% HNO 3 )。
After the addition of nitric acid is complete, the reaction mixture may be maintained under agitation so that mononitration is complete at room temperature. Mononitration is generally carried out at relatively low temperatures, but in this case the reaction mixture is heated to a relatively high temperature, for example above 50 ℃ and preferably above 55 ℃, as dinitration side reactions have been found to be advantageous. The reaction temperature is generally in the range of 55℃to 70℃such as 60℃to 65℃or 65℃to 70 ℃. In carrying out the nitration of 2-chloro-4-fluorobenzoic acid in the above temperature range, the reaction time should be adjusted to obtain a distribution of the desired isomer, undesired isomer and dinitro product in the crude product such as 80-90:3-10:3-10, e.g. 85-90:3-9:3-9 (HPLC, area%) respectively. The reaction time is, for example, not less than 3 hours, for example, not less than 4 hours, for example, from 4 to 7 hours (for example, about 5 to 6 hours).
For example, one variation of the process involves dissolving 2-chloro-4-fluorobenzoic acid in sulfuric acid, cooling the reaction mixture while at least 25%, such as 40% to 80% (about 50%) of H is present in molar excessNO 3 Nitric acid is added, the reaction mixture is heated to a temperature of not less than 55 ℃ and the reaction mixture is maintained at said temperature for at least 3 hours.
At the end of the reaction, the crude product is isolated by crystallization after addition of the reaction mixture to water (e.g. ice water) at a temperature of from 0 to 5 ℃ and subsequent separation of the solid from the aqueous medium, for example by filtration or centrifugation.
For this purpose, the contents of the reaction vessel are poured into ice water. The mixture is thoroughly stirred at a temperature of about 5 ℃ to 10 ℃ for at least 30 minutes, for example one to two hours, whereby the solid crude product is separated from the solution. It is desirable to use a relatively large volume of water to minimize yield loss due to incomplete precipitation, as it appears that the product exhibits some solubility in acidic aqueous media, e.g., a volume ratio in the range of 2-3 to 30 (water/reactant). The solids precipitated from the aqueous solution are recovered, for example, by solid/liquid separation techniques such as filtration and centrifugation, and dried.
It appears that the crude product absorbs a large amount of water during the work-up. By sucking on the filter for several hours we can remove the moisture from the crude product in a quite efficient way to a moisture level of about 18% to 20% (Karl Fischer titration). Such moisture levels were found to be acceptable for the next step, i.e. recrystallization from organic solvents. Other techniques for drying the crude product include vacuum drying in an oven or azeotropic distillation.
Next, the crude product (e.g., 85-90:3-9:9-3 ratio mixture) is purified by recrystallization from an organic solvent, i.e., solvent or solvent mixture, wherein the dinitro by-product exhibits relatively high solubility at room temperature or lower, i.e., relative to the mononitration isomer. Satisfactory solubility differences are observed in low-medium polarity solvents (e.g., having a solubility equal to or less than 20, e.g., in the range of from 2 to 20, e.g., from 2 to 10) at 20 ℃ -25 ℃, which are typically aprotic solvents such as aromatic hydrocarbons (e.g., alkylated aromatic hydrocarbons, e.g., toluene and xylene), halogenated aromatic solvents (e.g., chlorobenzene), esters (e.g., C2-C4 alkyl acetates), and ketones (e.g., methyl ethyl ketone). Purification by recrystallization is not limited to cooling crystallization or evaporative crystallization from a single solvent, and also includes the use of solvent pairs. For example from a mixture of ethyl acetate/toluene solvent of 5-15/85-95 by volume. The use of aliphatic hydrocarbons (e.g., heptane) alone is often inefficient, but mixtures of aliphatic hydrocarbons with moderately polar solvents (e.g., ethyl acetate or isopropanol) may be capable of achieving separation of products having high purity levels. In general, however, higher recovery can be achieved by cooling crystallization from alkylated aromatics, and this technique is generally preferred.
The ratio of aromatic hydrocarbon solvent to crude product required to achieve effective recrystallization is in the range of 3/1 to 10/1, such as 4/1 to 9/1, such as 5/1 to 8/1 (expressed as solvent per unit volume per unit weight of dry crude product, such as ml/g). Typical crude products consist of about 80-90:3-10:3-10 (HPLC, area%) of the desired isomer, the undesired isomer and the dinitro by-product, respectively. Efficient purification means achieving industrially acceptable yields (> 85%, e.g. > 90%) and low amounts of undesired isomer impurities (< 0.5%, e.g. < 0.1%) ]. The ratio between solvent and crude product is expected to vary depending on the type of solvent, target purity level and desired recovery, and will be adjusted accordingly. Toluene (5V to 7V), for example, has proven to be an effective solvent for recrystallization.
Drying of the recrystallized material may be performed in vacuo at 45-50 ℃ for several hours to achieve moisture levels of no more than 4%. There is no need to reduce the moisture level to, for example, 1%. 2-chloro-4-fluoro-5-nitrobenzoic acid appears to exhibit a degree of hygroscopicity because it tends to absorb water and return to a water level of about 4%.
The 2-chloro-4-fluoro-5-nitrobenzoic acid is recovered in a substantially pure form, i.e. free of undesired isomers, wherein the purity level (area% by HPLC) is not less than 97.0%, e.g. > 98.0%, > 99.0%, > 99.5%.
As indicated above, 2-chloro-4-fluoro-5-nitrobenzoic acid is useful as an intermediate in the synthesis of, inter alia, herbicidally active compounds such as pyribenzoxim shown below:
a process comprising converting the 2-chloro-4-fluoro-5-nitrobenzoic acid thus formed into a herbicidally active compound forms a further aspect of the invention.
Several synthetic routes can be used to obtain pyribenzoxim. For example, 2-chloro-4-fluoro-5-nitrobenzoic acid is reduced or hydrogenated to the corresponding amino compound 2-chloro-4-fluoro-5-aminobenzoic acid, for example by means of a metal reducing agent such as iron or zinc, in an organic solvent in the presence of an acid. For example, the reaction may take place in acetic acid as solvent using iron powder. 2-chloro-4-fluoro-5-aminobenzoic acid is then converted to an intermediate having the formula A1 as depicted below by coupling with 2-dimethylamino-4- (trifluoromethyl) -6h,1, 3-oxazin-6-one in acetic acid followed by alkylation in the presence of a base, for example to effect methylation at the free azauracil ring and the acid group (e.g. with methyl iodide and potassium carbonate in a polar aprotic solvent such as dimethylformamide), as shown in examples 3 and 4 of WO 01/83459:
for example, using BBr 3 As a deprotection agent, the ester intermediate having formula A1 is cleaved to give the corresponding benzoic acid. The deprotection reaction takes place in, for example, methylene chloride. The corresponding benzoic acid (chemical name 2-chloro-5- (3, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1 (2H) -pyrimidinyl) -4-fluorobenzoic acid, CAS number 120890-57-5) thus formed was collected as a white solid (identified herein as a compound having formula A2):
with acids, e.g. NH 2 -SO 2 -N[(CH 3 )(CH(CH 3 ) 2 )]To provide pyribenzoxim. The acid may be activated by conversion to acid chloride. However, it is more convenient to react the acid in the presence of Diazabicycloundecene (DBU) in tetrahydrofuran at reflux temperature in the presence of N, N-Carbonyldiimidazole (CDI).
Another important intermediate compound for the synthesis of pyribenzoxim is aminobenzoyl sulfonamide having the formula B1:
the preparation of the intermediate of formula B1 comprises 2-chloro-4-fluoro-5-nitrobenzoic acid with NH 2 -SO 2 -N[(CH 3 )(CH(CH 3 ) 2 )](i.e., N-methyl-N-isopropylsulfamide (CAS number: 372136-76-0)). The reaction may be carried out in Tetrahydrofuran (THF) as solvent in the presence of N, N' -Carbonyldiimidazole (CDI) and Diazabicycloundecene (DBU), as shown in example 54 of WO 01/83459, to give the corresponding nitrobenzoyl sulfonamide. Reduction of the nitro group using iron powder in, for example, acetic acid and THF as co-solvents as in the previously described synthetic routes gives aminobenzoyl sulphonamides of formula B1. It is also possible to hydrogenate the nitro groups with raney nickel in methanol (see hydrogenation procedure in example 31 of US 7,820,846). The preparation of intermediate B1 from acid is illustrated by the reaction scheme shown below:
a)CDI，DBU，THF，R＝NO 2 the method comprises the steps of carrying out a first treatment on the surface of the b) AcOH, fe powder, THF, or Raney Nickel, H 2 ，MeOH，R＝NH 2 。
Pyribenzoxim can be obtained from intermediates having formula B1 by a variety of routes.
For example, based on WO 01/83459, coupling an intermediate having formula B1 with 2-dimethylamino-4- (trifluoromethyl) -6h,1, 3-oxazin-6-one in acetic acid gives a desmethyl pyribenzoxim having formula B2:
other methods involve a cyclization step to form the uracil ring system.
One synthetic route is based on converting the amine group of the intermediate of formula B1 to isocyanate and coupling it with ethyl 3-amino-4, 4-trifluoro-2-butenoate. The preparation of phenyl isocyanate is described in US 7,820,846. Aminobenzoyl sulfonamide having formula B1 is treated with a phosgenation agent (phosgenating agent) to provide the corresponding phenyl isocyanate. US 7,737,275 describes the preparation of pyribenzoxim precursors (i.e. norpyribenzoxim) having the formula B2 by coupling them from isocyanate with enamine. The synthetic path is shown below:
the coupling of phenyl isocyanate to enamine is carried out under an inert atmosphere (water is removed from the reaction vessel by azeotropic drying prior to addition of benzoyl isocyanate). Different types of bases can be used, such as sodium hydride, potassium methoxide and potassium tert-butoxide, and potassium carbonate, such as MeOK in example 2 of US 7,737,275.
Another synthetic pathway is found in US 8,252,925, which involves a cyclization step to form the uracil ring system. The aminobenzoyl sulfonamide intermediate having formula B1 is treated with a solution of ethyl chloroformate (e.g., in methylene chloride in the presence of pyridine) to give the corresponding ethanolate (see example 1.2 of US 8,252,925). The ring closure is accomplished by reacting the ethanolate with ethyl 3-amino-4, 4-trifluoro-2-butenoate (e.g., in DMF) to form the uracil ring (see example 3.1.A of US 8,252,925). The resulting desmethyl pyribenzoxim of formula B2 is alkylated with dimethyl sulfate (e.g. in toluene/THF) in the presence of an aqueous base in the presence of a phase transfer catalyst to provide the target active ingredient (see example 3.3 of US 8,252,925). An exemplary synthetic pathway is shown below:
accordingly, the 2-chloro-4-fluoro-5-nitrobenzoic acid prepared according to the present invention can be used to produce pyribenzoxim by a process comprising the steps of:
a) Condensing 2-chloro-4-fluoro-5-nitrobenzoic acid with N-methyl-N-isopropylsulfamide to give nitrobenzoylsulfonamide, followed by reduction or hydrogenation of the nitro group to form an amine compound having formula B1;
b) Preparing a compound having formula B2 from a compound having formula B1 by:
b1 Coupling a compound having formula B1 with 2-dimethylamino-4- (trifluoromethyl) -6h,1, 3-oxazin-6-one; or alternatively
b2 A) converting the compound of formula B1 into isocyanate, for example by means of a phosgenation agent, and reacting the isocyanate with enamine; or alternatively
b3 Reacting a compound having the formula B1 with ethyl chloroformate, followed by coupling with enamine; and
c) The compound having formula B2 is methylated to provide pyribenzoxim.
Another way of synthesizing pyribenzoxim comprises the steps of:
a) Esterifying 2-chloro-4-fluoro-5-nitrobenzoic acid with an alcohol in the presence of, for example, thionyl chloride to give alkyl 2-chloro-4-fluoro-5-aminobenzoate:
wherein R is selected from the group consisting of: c which may be substituted by 1 or more substituents 1-12 Straight or branched alkyl (e.g. C 1-5 ) C which may be substituted by 1 or more substituents 3-10 Cycloalkyl, C which may be substituted by 1 or more substituents 6-10 Aromatic ring, C which may be substituted by 1 or more substituents 5-10 A heteroaromatic ring;
b) The alkyl 2-chloro-4-fluoro-5-nitrobenzoate is reduced or hydrogenated to form alkyl 2-chloro-4-fluoro-5-aminobenzoate. The reduction or hydrogenation reaction may be carried out in a suitable reactor, e.g. an autoclave, etc., with a conventional catalyst such as Pd on activated carbon, raney nickel, etc., using a different solvent, preferably an aprotic solvent, e.g. isopropyl acetate, THF, DMF, etc.:
c) The alkyl 2-chloro-4-fluoro-5-aminobenzoate is converted to the alkyl carbamate 2-chloro-4-fluoro-5-aminobenzoate. For example, the reaction of an alkyl 2-chloro-4-fluoro-5-aminobenzoate with ethyl chloroformate in the presence of N, N-diethylaniline gives the desired carbamate:
d) The carbamate alkyl 2-chloro-4-fluoro-5-aminobenzoate is cyclized to obtain 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoic acid alkyl ester. Cyclization was performed using 1, 8-diazabicyclo (5.4.0) undec-7-ene (DBU) and 3-amino-4, 4-trifluoro-but-2-enoic acid ethyl ester:
e) Alkyl 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoate is hydrolyzed to form 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoic acid. The hydrolysis may be carried out under usual conditions known in the art, for example under acid/base conditions in a protic or aprotic solvent, to give an acid of formula A3:
f) Combining the benzoic acid with NH 2 -SO 2 -N[(CH 3 )(CH(CH 3 ) 2 )]Coupled to provide a compound having formula B2:
g) Methylating the compound having formula B2 to provide pyribenzoxim.
Examples
HPLC method conditions: column: xbridge C18 (4.6X105) mm,3.5 μm; mobile phase-a: 10 ammonium bicarbonate aqueous solution; mobile phase-B: acetonitrile; gradient (T/%b): 0/10, 10/90, 15/90, 16/10, 20/10; flow rate: 1mL/min; a diluent: acetonitrile/water (1:1 v/v); injection volume: 5. Mu.L; run time: 20 minutes).
[ Relative Retention Time (RRT) of the undesired isomer was 1.22 and RRT of the dinitro isomer was 1.45].
Example 1
Preparation and purification of 2-chloro-4-fluoro-5-nitrobenzoic acid
A1L four-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser and thermocouple was charged with concentrated sulfuric acid (500 mL) and 2-chloro-4-fluorobenzoic acid (100 g,0.57 mol) at ambient temperature. Stirring the mixture for 10-15min to obtain a clear solution and cooling it to 10-15 ℃. Adding concentrated HNO dropwise 3 (54 g,0.86mol,1.5 eq.) and heating the resulting heterogeneous mixture to 60℃to 70 ℃. Monitoring on HPLC [ HPLC protocol includes: 1) 1ml of a sample taken from the reaction mixture is quenched in 1ml of ice-cold water, shaken for one minute, added with HPLC diluent (acetonitrile/water (1:1) mixture to obtain a clear solution, and analyzed by HPLC for detection of < 8% of undesired isomers and the gradual formation of dinitro by-products]The homogeneous reaction mixture formed is stirred at 60℃to 70℃for 5 to 6 hours. After the reaction was completed, the reaction mass was carefully poured into 2L of ice-cold water and kept at a temperature below 5℃to 10℃for 30 to 40min. Brown fumes were observed during quenching. The reaction mass is stirred at 5℃to 10℃for a further 1 to 2 hours, during which time the precipitation of the solid is complete, centrifuged and dried by rotation for a period of 1 to 2 hours.
The solid was added to toluene (500 mL) and the mixture was heated to 75-80 ℃ and stirred for 2-4h. The clear solution obtained was cooled slowly to room temperature and kept for 4-5h. Precipitate formed during cooling. The precipitate was isolated by vacuum filtration for 1-2 hours. The filtrate was collected for recovery and the filter cake was dried in vacuo at 45 ℃ -50 ℃ for 8h to obtain the desired isomer (89.0 g, 71.2%) with 99.6% purity by HPLC.
Example 2 (comparative) and examples 3-5 (inventive)
Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid:
effect of nitrifying agent
In a series of experiments, the procedure of example 1 was repeated, and the reaction was carried out at 55℃to 60℃to 70℃for three hours at different nitrifying doses. The composition of the crude product (desired isomer, undesired isomer and 3, 5-dinitro by-product) was determined by HPLC analysis and the results are listed in the following table.
TABLE 1
* Not detected
Example 6 (comparative), example 7 (inventive) and example 8 (comparative)
Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid:
influence of the reaction temperature
In a series of experiments, the procedure of example 1 was repeated, changing the reaction temperature: the reaction was run for four hours at 55-60 ℃ (example 6); the reaction was run for three hours at 60-65 ℃ (example 7); and 70 ℃ to 75 ℃, the reaction was carried out for four hours (example 8). The composition of the crude product (desired isomer, undesired isomer and 3, 5-dinitro by-product) was determined by HPLC analysis and the results are listed in the following table.
TABLE 2
Example 9 (comparative) and examples 10 to 12 (inventive)
Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid:
influence of the reaction time
In a series of experiments, the procedure of example 1 was repeated, changing the duration of the reaction, and the reaction continued for two hours (example 9); three hours (example 10), four hours (example 11) and 5 hours (example 12). The composition of the crude product (consisting of the desired isomer, the undesired isomer and the 3, 5-dinitro by-product) was determined by HPLC analysis and the results are presented in the following table.
TABLE 3 Table 3
Examples 13A-13D (comparative)
Preparation and purification of 2-chloro-4-fluoro-5-nitrobenzoic acid: mononitration and no dinitration side reaction
A1L four-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser and thermocouple was charged with concentrated sulfuric acid (500 mL) and 2-chloro-4-fluorobenzoic acid (100 g,0.57 mol) at ambient temperature. The mixture was stirred for 10-15min to obtain a clear solution and cooled to 0-5 ℃. Adding concentrated HNO dropwise 3 (43 g,0.69mol,1.2 eq.) and the mixture was warmed and stirred at room temperature for 1-1.5h under HPLC monitoring.
After completion, 1L of ice water was added to the reaction mixture. The resulting suspension was stirred at 0-5 ℃ for 1h, allowed to warm to ambient temperature and filtered. The filter cake was washed with 200mL of water and dried in vacuo. The solids consisted of 86.35% of the desired isomer and 12.22% of the undesired isomer, respectively, and contained no detectable amount of 3, 5-dinitro by-product.
The typical crude product obtained by the procedure described above was purified by a series of experiments performed by recrystallisation from a solvent pair (isopropyl alcohol/n-heptane). Experimental data (crude weight, ratio of solvent in solvent mixture by volume and recrystallization conditions) are listed in the following table.
TABLE 4 Table 4
Crude products consisting of mononitration isomer mixtures which are free of dinitro derivatives are difficult to purify by recrystallisation from isopropyl alcohol/n-heptane systems. For example, under the conditions of examples 13A and 13B, reasonable recovery was observed but product purity was unacceptable (94% and 87%, respectively). Recrystallization according to examples 13C and 13D provided highly pure product, but recovery percentages were poor (20% and 40%, respectively), and attempting to collect the second batch resulted in a significant drop in purity level.
Examples 14A-14F (Synthesis of pyribenzoxim)
Preparation of pyribenzoxim using 2-chloro-4-fluoro-5-nitrobenzoic acid as starting material
Example 14 A.2-chloro-4-fluoro-5-nitrobenzoic acid ethyl ester.
A clean dry 4-necked RBF (2000 mL) equipped with a mechanical stirrer, thermocouple, condenser and addition funnel was charged with 500mL of ethanol at 25℃to 30℃and 100g of 2-chloro-4-fluoro-5-nitrobenzoic acid, and the mixture was stirred for 10-15 minutes until a clear solution was obtained. The reaction mass was cooled to 0-5 ℃ and 108.6g thionyl chloride (2.0 eq.) was fed to the reaction mass at 0-5 ℃ for about 30 minutes. Thereafter, the reaction mass was slowly heated to 65-70 ℃ and stirred at this temperature while the solvent was gently refluxed at 65-70 ℃ for 6-8 hours. The reaction was monitored by HPLC area% analysis until the residual concentration of 2-chloro-4-fluoro-5-nitrobenzoic acid was less than 1%. After the reaction was completed, about 400mL of ethanol was distilled off under reduced pressure at 60℃to 65 ℃. The reaction mass was cooled to 20-25 ℃ and 500mL of water was added to the reaction mass at 20-25 ℃ over a period of 15-20 minutes. After that, 500mL isopropyl acetate was immediately added to the reaction mass and the mixture was stirred for 15-20 minutes. The layers were separated at 25-30 ℃. The top isopropyl acetate layer contained the product. The isopropyl acetate solution was washed with 100ml of 2% aqueous sodium bicarbonate solution. After phase separation, the isopropyl acetate solution of ethyl 2-chloro-4-fluoro-5-nitrobenzoate can be delivered to the next step (hydrogenation of the nitro group) without additional purification and/or product isolation. The yield of ethyl 2-chloro-4-fluoro-5-nitrobenzoate was 98%.
Example 14 B.5-amino-2-chloro-4-fluorobenzoic acid ethyl ester.
The isopropyl acetate solution of ethyl 2-chloro-4-fluoro-5-nitrobenzoate from example 14A was introduced into a clean and dry pressure reactor equipped with a mechanical stirrer, pressure gauge and thermocouple at 25 ℃ -30 ℃. To this solution was added 15g of Raney Ni under a nitrogen atmosphere at the same temperature. The reactor was closed and hydrogen pressure was applied to 90-100PSI at 25℃to 30 ℃. The mixture was stirred at 25-30 ℃ for 26-30 hours under the same hydrogen pressure until the concentration of both starting material and hydroxylamine intermediate was reduced to below 1 area% according to HPLC. At the end of the reaction, the catalyst was filtered from the reaction mass through a bed of celite at 25 ℃ to 30 ℃ under a nitrogen atmosphere. The bed was washed with 100mL isopropyl acetate at 25℃to 30 ℃. 200mL of isopropyl acetate was added to the combined isopropyl acetate solution, and the same volume of solvent was distilled off at 80℃to 85℃under atmospheric pressure to dry the reaction mixture until the moisture content level was 0.5% as analyzed by the KF method. The reaction mass was cooled to 25 ℃ to 30 ℃ and analyzed. A solution of ethyl 5-amino-2-chloro-4-fluorobenzoate in isopropyl acetate can be delivered to the next step (carbamate preparation) without additional purification and/or product isolation. The yield of ethyl 5-amino-2-chloro-4-fluorobenzoate was 95%.
Example 14 C.2-chloro-5-ethoxycarbonylamino-4-fluorobenzoic acid ethyl ester.
To a solution of ethyl 5-amino-2-chloro-4-fluorobenzoate from example 14B in isopropyl acetate was added 102.5g of n, n-diethylaniline at 25 ℃ -30 ℃. 74g of ethyl chloroformate were fed drop-wise to this mixture at 25℃to 30℃over a period of 15 to 20 minutes. The reaction mass was heated to 40-45 ℃ and maintained at this temperature for 6-8 hours until the starting material concentration was reduced to less than 1 area% by HPLC. Towards the end of the reaction, a solid precipitate was observed. The reaction mass was cooled to 25 ℃ to 30 ℃ and 300ml 10% hcl was added at this temperature. The reaction mass is stirred at 25-30 ℃ for 30-40 minutes and the two layers are then separated. The aqueous layer was sent for recovery of N, N-diethylaniline. The upper organic layer was washed with 100mL of 5% aqueous sodium bicarbonate solution and analyzed. A solution of ethyl 2-chloro-5-ethoxycarbonylamino-4-fluorobenzoate in isopropyl acetate can be delivered to the next step (cyclization) without additional purification and/or product isolation. The yield of ethyl 2-chloro-5-ethoxycarbonylamino-4-fluorobenzoate was 97%.
Example 14 D.2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoic acid ethyl ester.
The isopropyl acetate solution of ethyl 2-chloro-5-ethoxycarbonylamino-4-fluorobenzoate from example 14C was charged to a clean and dry RBF and a substantial portion of the isopropyl acetate (about 300-350 mL) was distilled off at 600-625 mbar at 55-60 ℃. 300mL of N, N-dimethylacetamide was added to the residue, and distillation of isopropyl acetate was continued under the same conditions. Near the end of the distillation, 200mL of toluene was added to the mixture, and the mixture was dried by azeotropic distillation of toluene under vacuum at 60 ℃ to 70 ℃. The residual water content must not exceed 0.5% (by KF). To a dry solution of ethyl 2-chloro-5-ethoxycarbonylamino-4-fluorobenzoate in N, N-dimethylacetamide was added 104.4g of 1, 8-diazabicyclo (5.4.0) undec-7-ene (DBU) and 100.8g of ethyl 3-amino-4, 4-trifluorobut-2-enoate at 25℃to 30 ℃. The reaction mass was heated to 58-62 ℃ under a nitrogen stream to better remove ethanol formed in the reaction. The reaction mass was stirred under these conditions for 12-14 hours such that the concentration of ethyl 2-chloro-5-ethoxycarbonylamino-4-fluorobenzoate was reduced to below 2 area% by HPLC. The reaction mass was cooled to 25 ℃ to 30 ℃ and poured into 500ml of 10% aqueous HCl at a temperature of 10 ℃ to 15 ℃. The temperature was raised by 4-5 ℃ and the reaction mass was warmed to 25-30 ℃ with stirring. 1000mL of isopropyl acetate was added to the mixture and stirring was continued for 30-40 minutes at 25℃to 30 ℃. The layers were separated at 25-30 ℃. Isopropyl acetate contains the product. The solution of ethyl 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoate in isopropyl acetate can be delivered to the next step (hydrolysis) without additional purification and/or product isolation. The yield of ethyl 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoate was 85%.
Example 14 E.2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoic acid.
A solution of ethyl 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoate from example 14D in isopropyl acetate was delivered to a clean RBF at 25 ℃ to 30 ℃ and about 850mL of isopropyl acetate was distilled off at 45 ℃ to 50 ℃ under reduced pressure. 600mL of dioxane was added to the mixture, and about 100mL of dioxane was distilled off under vacuum at 55℃to 60℃along with the remaining isopropyl acetate. 1000mL of concentrated HCl was slowly fed to the reaction mass at 25℃to 30 ℃. The reaction mass was heated to 90 ℃ to 95 ℃ and stirred under these conditions for 22 to 24 hours until the ethyl 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoate concentration was reduced to less than 2 area% by HPLC. At the end of the reaction, dioxane was distilled off under reduced pressure at 55℃to 60 ℃. The reaction mass was cooled to 25 ℃ to 30 ℃ and 700mL of water was added at the same temperature. Stirring was continued for 4-6 hours at 20-25 ℃. The reaction product was filtered at 25 ℃ to 30 ℃ and washed with 400mL of water at 25 ℃ to 30 ℃. 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoic acid having a purity of not less than 96 area% by HPLC is prepared. The wet compound was dispersed in 500mL of toluene and the mixture was dried by azeotropic distillation at 100 ℃ to 110 ℃ until the moisture content in the reaction mass was no more than 0.5% (by KF). The reaction mass was cooled to 20-25 ℃ and stirred at this temperature for 3-4 hours. 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoic acid is filtered at 20℃to 25℃and dried under reduced pressure at 45℃to 50 ℃. 108g of product are isolated, the content being 97%. The yield of the hydrolysis step was 86%, or the yield of the five nesting steps (telescopic step) was 66%.
Example 14 F.2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluoro-N- (N-isopropyl-N-methylsulfamoyl) benzamide.
/>
A clean, dry 4-necked RBF equipped with a mechanical stirrer, thermocouple, condenser and addition funnel was charged with 40ml of acetonitrile, 13g N-isopropyl-N-methylaminosulfonamide and 15.75g of potassium carbonate at 25℃to 30℃under a nitrogen atmosphere. The reaction mass was heated to 55 ℃ to 60 ℃.
Another RBF was charged with 100mL of acetonitrile and 20g of 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoic acid from example 14E and 12g of 1,1' -Carbonyldiimidazole (CDI) were added under nitrogen at 25℃to 30 ℃. The reaction mass was heated to 55 ℃ to 60 ℃ and stirred at this temperature for about 1.5H to produce 3- (4-chloro-2-fluoro-5- (1H-imidazole-1-carbonyl) phenyl) -6- (trifluoromethyl) pyrimidine-2, 4 (1H, 3H) -dione. The residual concentration of 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoic acid was less than 2 area% by HPLC.
The prepared 3- (4-chloro-2-fluoro-5- (1H-imidazole-1-carbonyl) phenyl) -6- (trifluoromethyl) pyrimidine-2, 4 (1H, 3H) -dione was reacted at 55℃to 60℃over a period of 10 to 15 minutesIs fed into a mixture of N-isopropyl-N-methylaminosulfonamide and potassium carbonate. The reaction mass was stirred at 55-60 ℃ for 6-8 hours until the concentration of 3- (4-chloro-2-fluoro-5- (1H-imidazole-1-carbonyl) phenyl) -6- (trifluoromethyl) pyrimidine-2, 4 (1H, 3H) -dione was no more than 2 area% by HPLC. At the end of the reaction, the mixture is cooled to 25℃to 30℃and stirred at this temperature for 25 to 30 minutes. K is added at 25-30 DEG C 2 CO 3 The reaction mass was filtered and washed with 20mL acetonitrile. The filtrate (containing the product) was charged to a clean RBF and heated to 40 ℃ -45 ℃. About 80mL of acetonitrile was distilled from the filtrate at 40-45 ℃ under reduced pressure (650 mbar). The reaction mass was cooled to 25 ℃ to 30 ℃ and 200mL of 2-methyl-THF and 100mL of water were added immediately. The reaction mass was cooled to 0-5 ℃ with good stirring and the pH of the reaction mass was adjusted to 1-2 with concentrated HCl (about 25 mL) at the same temperature. Cooling and stirring was stopped and the layers were separated at 25-30 ℃. The top organic layer contained the product. The bottom aqueous layer contained imidazole hydrochloride. The top organic layer was charged to a clean RBF and 60mL of water was added at 25 ℃ -30 ℃. The pH of the aqueous phase was adjusted to 5.8-6.0 with 5% aqueous sodium bicarbonate with good stirring. The layers were separated at 25-30 ℃. The top organic layer contained the product. The bottom aqueous layer contained the sodium salt of 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoic acid. The top organic layer was charged to a clean RBF and about 160ml of 2-methyl THF was distilled off under reduced pressure at 40 ℃ -45 ℃. 60mL of toluene was added to the residue, and another about 30mL of solvent (mainly remaining 2-methyl THF) was distilled off under the same conditions. The reaction mass was cooled and stirred at 25 ℃ to 30 ℃ for 1 to 2 hours. The precipitated solid was filtered and washed with 20ml toluene at 25-30 ℃. The wet solids were charged to a clean RBF and 40ml of acetone was added at 25℃to 30 ℃. The mixture was stirred at 25 ℃ to 30 ℃ for 30 minutes and 100mL of water was slowly fed at the same temperature. The mixture was stirred for 4 hours to allow the product to crystallize completely and the solid compound was filtered at 25-30 ℃. After drying at 50℃to 55℃under reduced pressure for 10 to 12 hours 19g of 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluoro-N- (N-isopropyl) are preparedphenyl-N-methylsulfamoyl) benzamide. The yield was 70%.
The next step (methylation to provide pyribenzoxim) can be carried out by using prior art examples, for example the examples disclosed in WO 2001/083459.

Claims (14)

1.A method, the method comprising the steps of:
reacting 2-chloro-4-fluorobenzoic acid with a nitrating agent;
separating a crude reaction product consisting of 2-chloro-4-fluoro-5-nitrobenzoic acid, 2-chloro-4-fluoro-3-nitrobenzoic acid and 3, 5-dinitro-2-chloro-4-fluorobenzoic acid;
purifying the crude reaction product; and
obtaining 2-chloro-4-fluoro-5-nitrobenzoic acid in substantially pure form.
2. The method of claim 1, wherein the amount of nitrating agent, reaction temperature, and reaction time are selected to adjust the ratio of 2-chloro-4-fluoro-3-nitrobenzoic acid to 3, 5-dinitro-2-chloro-4-fluorobenzoic acid in the range of 3:1 to 1:3 (HPLC, area%).
3. The process according to claim 1 or 2, wherein the nitrating agent is a nitric/sulfuric acid mixture with a molar excess of HNO relative to 2-chloro-4-fluorobenzoic acid of at least 25% 3 。
4. A method according to claim 3, comprising combining
2-chloro-4-fluorobenzoic acid is dissolved in sulfuric acid, nitric acid is added while keeping the reaction mixture cool, the reaction mixture is heated to a temperature of not less than 55 ℃, and the reaction mixture is maintained at the temperature for at least 3 hours.
5. The process according to any one of claims 1 to 4, wherein the crude product is isolated by crystallization after addition of the reaction mixture to cold water followed by separation of the crude solid product from the aqueous medium.
6. The process of claim 5, wherein the isolated crude product is a 85-90:3-9:9-3 ratio mixture (HPLC, area%).
7. The process of any one of claims 1 to 6, wherein the crude product is purified by recrystallization from one or more solvents.
8. The method of claim 7, wherein the one or more solvents are selected from the group consisting of: aromatic hydrocarbon solvents, halogenated aromatic solvents, ester solvents, and ketone solvents.
9. The method of claim 8, wherein the solvent is an alkylated aromatic hydrocarbon.
10. The process of claim 9, wherein the ratio of the aromatic hydrocarbon solvent to the crude product is in the range of 4/1 to 9/1.
11. The method of any one of the preceding claims, further comprising converting 2-chloro-4-fluoro-5-nitrobenzoic acid to a compound having herbicidal activity.
12. The method according to claim 11, comprising the steps of:
reducing or hydrogenating 2-chloro-4-fluoro-5-nitrobenzoic acid to obtain 2-chloro-4-fluoro-5-aminobenzoic acid;
converting 2-chloro-4-fluoro-5-aminobenzoic acid to an ester compound having the formula A1:
cleaving the ester of formula A1 to the corresponding benzoic acid of formula A2:
and
bringing said benzoic acid A2 into contact with NH 2 -SO 2 -N[(CH 3 )(CH(CH 3 ) 2 )]To provide pyribenzoxim.
13. The method according to claim 11, comprising the steps of:
a) Condensing the 2-chloro-4-fluoro-5-nitrobenzoic acid with N-methyl-N-isopropylsulfamide to give nitrobenzoylsulfonamide, followed by reduction or hydrogenation of the nitro group to form an amine compound having formula B1;
b) Preparing a compound having formula B2 from the compound having formula B1 by:
b1 Coupling the compound having formula B1 with 2-dimethylamino-4- (trifluoromethyl) -6h,1, 3-oxazin-6-one; or alternatively
b2 Converting the compound of formula B1 to the corresponding isocyanate and reacting the isocyanate with an enamine; or alternatively
b3 Reacting the compound of formula B1 with ethyl chloroformate, followed by coupling with an enamine; and
c) Methylating the compound having formula B2 to provide pyribenzoxim.
14. The method according to claim 11, comprising the steps of:
a) Esterifying 2-chloro-4-fluoro-5-nitrobenzoic acid with an alcohol to give alkyl 2-chloro-4-fluoro-5-nitrobenzoate:
wherein R is selected from the group consisting of: c which may be substituted by 1 or more substituents 1-12 Straight-chain or branched alkyl, C which may be substituted by 1 or more substituents 3-10 Cycloalkyl, C which may be substituted by 1 or more substituents 6-10 Aromatic ring, C which may be substituted by 1 or more substituents 5-10 A heteroaromatic ring;
b) Reduction or hydrogenation of alkyl 2-chloro-4-fluoro-5-nitrobenzoate to form alkyl 2-chloro-4-fluoro-5-aminobenzoate:
c) Conversion of alkyl 2-chloro-4-fluoro-5-aminobenzoate to alkyl carbamate 2-chloro-4-fluoro-5-aminobenzoate:
d) Cyclizing the carbamate alkyl 2-chloro-4-fluoro-5-aminobenzoate to obtain 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoic acid alkyl ester:
e) Hydrolyzing the alkyl 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoate to form a 2-chloro-5- (2, 6-dioxo-4- (trifluoromethyl) -3, 6-dihydropyrimidin-1 (2H) -yl) -4-fluorobenzoic acid having the formula A3:
f) Bringing the benzoic acid of formula A3 into contact with NH 2 -SO 2 -N[(CH 3 )(CH(CH 3 ) 2 )]Reaction to give a compound of formula B2:
and
g) Methylating the compound having formula B2 to provide pyribenzoxim.
CN202280023580.9A 2021-03-26 2022-03-22 Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid Pending CN117062805A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN202131013524 2021-03-26
IN202131013524 2021-03-26
PCT/IL2022/050321 WO2022201155A1 (en) 2021-03-26 2022-03-22 Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid

Publications (1)

Publication Number Publication Date
CN117062805A true CN117062805A (en) 2023-11-14

Family

ID=81326370

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202280023580.9A Pending CN117062805A (en) 2021-03-26 2022-03-22 Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid

Country Status (5)

Country Link
EP (1) EP4313954A1 (en)
CN (1) CN117062805A (en)
BR (1) BR112023019613A2 (en)
IL (1) IL305851A (en)
WO (1) WO2022201155A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023017518A1 (en) * 2021-08-09 2023-02-16 Adama Agan Ltd. A new process of saflufenacil production using novel intermediates
WO2024047648A1 (en) * 2022-08-31 2024-03-07 Adama Agan Ltd. Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1226127B1 (en) 2000-05-04 2009-07-01 Basf Se Substituted phenyl sulfamoyl carboxamides
UA89941C2 (en) 2002-10-30 2010-03-25 Басф Акциенгезелльшафт Phenyliso(thio)cyanates, processes and intermediates for their preparation
US7737275B2 (en) 2003-12-03 2010-06-15 Basf Aktiengesellschaft Method for producing 3-phenyl(thio)uracils and 3-phenyldithiouracils
UA83764C2 (en) 2004-07-22 2008-08-11 Басф Акциенгезелльшафт Method for the production of 3-phenyl(thio)uracils and dithiouracils and carbamate used therein
CN106905161B (en) * 2017-03-09 2019-03-01 常州沃腾化工科技有限公司 A kind of synthetic method of 2- chlorine-4-fluorine-5-nitro benzoic acid

Also Published As

Publication number Publication date
EP4313954A1 (en) 2024-02-07
WO2022201155A1 (en) 2022-09-29
IL305851A (en) 2023-11-01
BR112023019613A2 (en) 2023-11-14

Similar Documents

Publication Publication Date Title
CN117062805A (en) Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid
US8058432B2 (en) Method for preparing phenylalanine derivatives having quinazoline-dione skeleton and intermediates for use in the preparation of derivatives
US6166208A (en) Preparation of fungicidal quinazolinones and useful intermediates
US11739057B2 (en) Polymorphic forms of Belinostat and processes for preparation thereof
US8884046B2 (en) Compounds useful in the synthesis of benzamide compounds
JPH0832675B2 (en) Biuret and its manufacturing method
US6936720B2 (en) Method for preparing benzisoxazole methane sulfonyl chloride and its amidation to form zonisamide
JP2682705B2 (en) A method for producing a 2,6-dichlorophenylaminobenzeneacetic acid derivative and a diphenylamine derivative.
JPH0250110B2 (en)
CN117794897A (en) Novel process for producing pyribenzoxim using novel intermediates
US7390899B2 (en) Process for the synthesis of high purity 3,5-diamino-6-(2,3-dichlorophenyl) (1,2,4-triazine)
JP4001397B2 (en) Process for producing substituted aminocarbonyltriazolinones
WO2024047648A1 (en) Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid
EP0273321A1 (en) 7-Bromo-beta-carboline compound and method for producing same
JP2006512305A (en) Process for producing 2-amino-4-chloro-6-alkoxypyrimidine
KR100420494B1 (en) Preparation of 2-trifluoromethoxybenzenesulfonamide
US20030069423A1 (en) Novel processes for the preparation of adenosine compounds and intermediates thereto
US7145014B2 (en) Process for the preparation of quinoline derivatives
KR100596668B1 (en) Process for preparing alkoxytriazolinones
WO2023100110A1 (en) Process for preparing brivaracetam
WO2003101971A1 (en) Process for preparing (s)-tetrahydro-a-(1-methylethyl)-2-oxo-1(2h)- pyrimidineacetic acid
JP2000504675A (en) Method for producing substituted cyanophenyluracil from substituted aminoalkenoic cyanophenylamides
JPS62123162A (en) Production of cyano-substituted aniline compound
EP1344775A1 (en) Preparation of fungicidal quinazolinones and useful intermediates
JP2005343867A (en) Method for producing 5-amino-1-substituted-1,2,4-triazole, and triazole derivative obtained by the production method

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination